ART (agouti related transcript) was originally discovered as an mRNA that is upregulated in the hypothalamus of ob/ob and db/db mice. The ART gene has been cloned from both mice and humans and encodes a protein of 131 amino acids in mice and 132 amino acids in humans (Shutter et al., 1997, Genes and Development 11:593-602). Recombinantly produced ART protein has been shown to be a functional antagonist of the melanocortin-3 receptor (MC3R) and the melanocortin-4 receptor (MC4R) (Fong et al., 1997, Biochem. Biophys. Res. Comm. 237:629-631; Ollman et al., 1997, Science 278:135-138).
MC3R and MC4R belong to a class of G-protein coupled receptors known as the melanocortin receptors, since these receptors activate adenylyl cyclase in response to ligands known as melanocortins (e.g., adrenocorticotrophin (ACTH) and the α-, β-, and γ-melanocyte stimulating hormones). MC3R and MC4R are neural melanocortin receptors, with MC3R being expressed in the hypothalamus and limbic system of the brain and MC4R being expressed widely in the brain. In particular, MC4R expression has been found in a number of hypothalamic sites, including the ventromedial, lateral, dorsomedial, and paraventricular nuclei (Mountjoy et al., 1994, Mol. Endocrinol. 8:1298-1308), regions which have been shown to play a role in feeding behavior (Bray, 1987, Nutr. Rev. 45:3343). Gene targeting experiments have shown that MC4R has an important role in the control of feeding behavior and obesity. Knockout mice lacking MC4R develop an obesity syndrome characterized by hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar et al., 1997, Cell 88:131-141).
In view of this, there is great interest in the ART protein, which appears to be a natural regulator of MC3R and MC4R in humans. It is believed that the ART protein is likely to be a natural regulator of human obesity which functions by antagonizing either MC3R or MC4R. Accordingly, the identification of substances that inhibit the binding of ART protein to MC3R or MC4R is desirable, since such inhibitors are likely to be of value in the control of obesity. Substances that potentiate the effect of ART protein on MC3R or MC4R are also likely to be of value in the control of body weight.